This study identified novel predictors of IC toxicities in HNC using a verified cancer registry database. During the first cycle of taxane and platinum-based IC in HNC, up to 24% DLT events were recorded in our series. Docetaxel per kilogram LBM, pre-treatment GPT > 40 U/L and history of chronic liver disease were strongly associated with DLT events. For male HNC treated with IC, the abovementioned variables should be identified and high-risk group deserved closer follow-up and care.
Compared to other studies, our research has several strengths. The prediction ability of chemotherapy dose per kilogram LBM was first validated in HNC with taxane and platinum-based induction chemotherapy for DLT events . Although previous literature had used a similar concept, its application for toxicity event prediction was not widespread . Moreover, we have performed a comprehensive analysis for DLT events. Variables like patients’ characteristics, laboratory data, inflammation markers, body composition factors, and chemotherapy dose were all included. In addition, the correctness of our data was validated. The Cancer Registry System in Taiwan is supervised by the Health Promotion Administration of the Ministry of Health and Welfare. They regularly monitor data correctness and implement the accreditation of cancer centers every three years .
Several hematological inflammatory markers, such as the C-reactive protein-to-albumin ratio, modified Glasgow Prognostic Score, neutrophil to lymphocyte ratio, and platelet-to-lymphocyte ratio, have been used to predict IC toxicity in HNC . The plausible mechanism for the toxicity is attributed to poor nutrition, inflammation, and immune suppression. However, a significant drawback was that body mass index (BMI) was the sole body composition factor in their statistical analyses. Besides of BMI, body composition factor, like a low SMI or LBM, has been reported to yield adverse effects on chemotherapy dose-limiting toxicity. More specifically, a low SMI is suggested to be related to a chemotherapy dose reduction of ≥ 50% due to neutropenia or nephrotoxicity, a treatment postponement ≥ 4 days in the case of bone marrow suppression, or definitive chemotherapy termination after the 1st or 2nd chemotherapy cycles in HNC patients receiving definitive chemoradiotherapy . Our previous study has documented the adverse prognostic effects of sarcopenia on overall survival (aHR: 1.74; 95% CI: 1.14–2.67) and disease-specific survival (aHR: 1.67; 95% CI: 1.04–2.67) in oral cancer patients, and the negative effect was even more significant among patients aged < 60 years .
Our study revealed that the chemotherapy dose per kilogram LBM, like docetaxel per kilogram LBM more than 2.52 mg/kg could be a significant toxicity predictor in male HNC patients. The primary toxicity mechanism might be chemotherapy overdose in specific populations, such as in sarcopenia or myopenia . Most chemotherapy dosages are determined by BSA, while some have a fixed or capped dose (e.g., carboplatin). Given the BSA-based dose calculation formulae, patients having a similar BSA but with a lower LBM were treated with a higher dose of chemotherapy per LBM. This phenomenon was more prominent in docetaxel than cisplatin cases, which was expected from a pharmacokinetic perspective. Increased adipose tissue denotes a higher distribution for and uptake of lipid-soluble drugs, such as docetaxel, and a lower distribution for water-soluble drugs such as cisplatin [24–26]. This difference explains why patients with a smaller muscle proportion and a higher adipose tissue proportion were more prone to docetaxel toxicities, as both the protective effect of muscle and the negative effect of excess adipose tissue are contributory .
Toxicities are sometimes indicative of adequate chemotherapy dose, which may be associated with better outcomes in solid tumor cancers, such as gastric cancer, non-small cell lung cancer, and prostate cancer [28–30]. However, toxicities could also result in postponement or termination of chemotherapy, resulting in worse outcomes . In our study, HNC patients with significant toxicities during induction chemotherapy were not associated with better response rates (58.8% in patients without toxicity event vs 50% in patients with toxicity event, P = 0.389; Supplementary table 5). The benefit of the toxicity event, a proxy of adequate chemotherapy dose per cycle might be offset by insufficient relative dose intensity (RDI) . Using our risk score, prophylactic protocol, like granulocyte-colony stimulating factor injection, or intensive care could be applied for the high-risk group in order to prevent DLT events and achieve acceptable RDI.
Our study has several limitations. We performed a retrospective study with the abovementioned data extracted from our electronic medical records. Although most laboratory data have been rechecked within one week of IC, some variations still existed. In addition, this retrospective study was designed to find new predictors instead of creating a new formula for chemotherapy dose modifications in clinical scenarios. Chemotherapy dose modifications require further large-scale, high-quality observational studies and clinical trials, such as cabazitaxel dose modification in prostate cancer . Moreover, the SMI or CSA at C3 was derived from head and neck CT, MRI, or PET scan images, rendering the possibility of inaccurate estimates. Nevertheless, previous literature has validated the interchangeability of CT- or MRI-derived imaging biomarkers of SMI . Finally, due to large variation of body composition factors and chemotherapy per kilogram LBM between the male and female patients, stratified analysis was performed and risk score for male HNC patients alone was established.